Difficultly dissociable acyl derivatives of salicylic acid and process of making same



Patented July 23, 1935 DIFFICULTLE-DISSOCIABLEiACYDsDERlVA s-TIVESgOF .SALICYLICtAQID:ANQ'PEOGESS ,fHansKaufmann; lMunster/Westphalia; Germany I This inventionconcerns a: process forithe preparation of diflicultly; dissociablenacyl derivatives of. gsfllicylicacid and its. derivatives.

The therapeutic use of the acyl derivative; of U 5 salicylic ;.,acid is, based: on theltheory, that the dissociationof this-,medicament, in the-organism icauses :iree acid, to act thereon. The greater the ease of dissociation of the acyl residue the greater is the ease-g with ,aWhiChi;1511181 1163. can t e-19 be carried into efiect. The easier the dissociation of acetyl salicylicacid the smaller is the percentage of the substance left unchanged.

In contradistinction thereto the object of the present invention is the preparation of materials 1 which are more stable than acetyl salicylic acid so that the molecule can more easily act as a 'izwhole. This higher stability is also useful from a-pracuca1' point 'of View; because suchmaterials are more durable and suitable forstorage.-

asAccordingltothe-processof the-.presentinvention difiicultly dissociable acyl derivatives of salicylic acid .or its derivatives are prepared by combining di-ethyl-acetic acid or brom-di-ethyl acetic acid with salicyliczacid or its esters by known methods. I

The materials, di-ethylacetyl salicylic acid and 1 1 2 1rdiaethvlace yl sa cylic. acidthus ,ph a ne have not hitherto been described,intheliterature.

7 They can be obtained according tothisinvention 5. by warious.*knownmethods, such as by reacting salicyclic acid or sodium salicylate with the acid' chlorides with or without the assistance of a hydrochloric acid-binding agent, or from salicylic acid and the anhydrides of the acids to be used,

for acylation. It is important to avoidan excess of salicylic acid since difiiculties will otherwise be encountered in the crystallization. It is preferable to make use of the method of preparation from acid chlorides and salicylic acid in the presence of pyridine.

The properties of the new compounds thus obtained are described in detail in the, examples. They fulfill the desideratum of being more difficultly saponifiable, which could not be foreseen. If, for example, equivalent amounts of the new acids are compared with acetyl salicylic acid with respect to their dissociation by N/lO soda lye, it will be found that the latter is completely dissociated in 5 minutes, whereas in the case of brom-di-ethylacetyl salicylic acid 2 hoursare required and in the case of di-ethyl-salicylic acid as long as 8 hours are required. The new compounds can also if required be exposed for a long time to damp air, or be kept in tablet form, without any decomposition setting in.

sNo;":Dr.aW glAn catio S nt mh S LN 9523.6 n em J aoc ai s.

, somhothofat e atorementionedacids espondina alts. nebaobtain cti rknown ma ,e Wh 1 ,.-as is -;kn wn.:..acety1;.;salicyl a-ac d s.n .t -pr d ee perma nt. so ium ompoun 1 .di-et ylace l a c ;.ac d doesrrqelucea compoundse asesalso m asauinin v asalt it; s esire repare .ste of t new. om qundsyt i corr nopd p -r -.salicylic ee i emnl xecle t l.

terials r p \I. The following examples illustrate how the process ofthe invention may be carried intoeifect:

1-.12Q-partsof di-ethylacetyl-chloride are slowly introduced into a solution-containing 22 parts of salicylic'acid in ether,'to whichpyridine has? been added. Aiftr allowing it to stand'for several '..l1ours;;.the; product; of theireactioniisaponreditint ice-cold hydrochloric.acidanditheaether.=,s 1uti n washed several times with watensaAfterifiyap rating 01? the ether, the residue left behind. is di-ggi wgestedawith 'warmwazter, orpreferablyimithi 2 alcohol; until the.saiic ciicacid-re ctionidise {.pears. atheiadryi product is; orystal ized-i riomingli f a: ;1leum.--ether. aiIhe dieethylacetyl ,salicyclic a,:thus .zobtainedhas, 'a melting. pointQot-L 5 .very diflicultly soluble in; waterabuaeasilpsoluble .-in.the;;usua1 organiclsolvents; .iAbQ tsolvesi'inshotsanimal. oryegeiable 11 nd 1110 %iin coldanimalorrvegetable oil.. v

pound is shaken up with dry sodium carbonate and the solvent evaporated or removed with ether, the sodium salt of diethyl-acetyl salicylic acid is obtained; it is soluble in water and alcohol and insoluble in ether, acetone and chloroform. The 3;; calcium salt, which can be obtained in a similar manner, is, however, on the contrary difficultly soluble in water, more easily soluble in alcohol and benzene and readily sol form.

If molecular quantities of di-ethylacetylsalicylic acid and quinine are dissolved in absolute alcohol, there remains, after the solvent has been removed by evaporation, the quinine salt of diethylacetyl salicylic acid in the formof a White 5 powder. That a combination in molecular proportions of the components is produced can be proved by carrying out the experiments with the use of an excess of di-ethylacetyl salicylic acid. The latter can be washed out with a sufilcient 50 quantity of petroleum ether and'the uniform compound remains behind.

2. 14 parts of salicylic acid dissolved in ether containing pyridine were reacted drop by drop with 21 parts of brom-di-ethylacetyl chloride. 55.

If the methyl alcohol solution.oiztbfilinswiiifil ww uble in acetone afidichloro- After allowing the mixture to stand for some hours the pyridine or pyridine hydrochloride is removed by washing with water. The solution is dried and crystallized out. The brom-di-ethylacetyl salicylic acid which has a melting point of 88-89 C. is crystallized from petroleum ether. It is diflicultly soluble in water but soluble in most organic solvents. Salts and'compounds with organic bases can be produced in known manner.

3. 15 parts of salicylic acid methyl ester and 13 parts of di-ethylacetyl chloride are reacted to gether in solution in ether; preferably in the presence of pyridine. product di-ethylacetyl salicylic acid methyl ester is produced, having a boiling point of 140-14? C. under a pressure of 3 mm. of mercury. The product is a colorless, oily, almost odorless liquid. In the same way the amyl ester can be produced as a water clear liquid having a boiling point of 180 C. under a pressure of 3 mm. of mercury. v

4. Following the method of Example 3, 15 parts of'salicylic acid methyl ester and 21 parts of broml OOC-C-H OOCCH A and l 2114 CzHa COOR COOR di-etliylacetyl chloride were reacted to produce brom-di-ethylacetyl salicylic acid methyl ester.

- It distils under a 3mm. vacuum at 175 C., as a colorless, faintly odorous liquid.

Generalizing the above, it will be seen that the substances involved in the present case may be expressedin symbols by the following formulas, de-

noting acyl derivatives of salicylic acid:-

wherein X represents hydrogen or bromine and R represents hydrogen, a lower alkyl or an alkaliforming metal.

I claim:

1. A process for the production of diflicultly dissociable acylder'ivatives of salicylic acid comprising reacting consisting of acetic acid anhydride, brom-di-ethyl acetyl a substance selected fromthe group di-ethyl acetic acid, .brom-di-ethyl acetic acids, di-ethyl acetyl chloride, (ii-ethyl chloride and brom-di-ethyl acetic acid anhydride with a substance selected from the group consist-.

ing of salicylic acid, salicylic acid esters and salicylic acid salts.

By working up the reaction 2. A process for the production of difficultly dissociable acyl derivatives of salicylic acid comprising reacting a substance selected from the group consisting of di-ethyl acetic acid, brom-di-ethyl acetic acid, di-ethylacetyl chloride, di-ethyl acetic acid anhydride, brom-di-ethylacetyl chloride and brom-di-ethyl acetic acid anhydride with a substance selected from the group consisting of salicylic acid, salicylic acid esters and salicylic acid salts in the presence of an acid-neutralizing agent. 10 agent.

3. A process for the production of difficultly dissociableecyl derivatives of salicylic acid comprising reacting a susbtance selected from the group consisting of .di-ethyl acetic acid, brom-diethyl acetic acid, di-ethylacetyl chloride, di-ethyl acetic acid anhydride, brom-di-ethylacetyl chloride and brom-di-ethyl acetic acid anhydride with wherein X represents hydrogen or bromine and R represents hydrogen, a lower alkyl or an alkaliforming metal. 7 i

- 10. A compound'having the general formula 40 o'0o-( i11 COOR [245 wherein R represents hydrogen, a lower alkyl or an alkali-forming metal.

. HANS KAUFMANN. 

